Women of African ancestry (AA) are more likely than women of European ancestry (EA) to be diagnosed with breast cancer before age 45, and to have more aggressive tumors, characterized by negativity for estrogen, progesterone and HER-2 receptors (triple negative). Younger AA women are more than twice as likely as EA women to be diagnosed with basal-like breast tumors, an intrinsic subtype with poor prognosis. The reasons for these racial disparities are unclear, and existing studies of AA women lack the statistical power to investigate risk factors for breast cancer defined by early age at onset and tumor biology. We hypothesize that evolution over millennia in Africa resulted in genetic profiles encoding specific phenotypes, such as robust inflammatory/immune response to withstand endemic infectious disease, and higher skin melanin content to protect from UV radiation, but that these factors may increase risk of aggressive tumors, particularly in the context of life in the northern hemisphere or in a more urban environment. Specifically, we hypothesize that early onset aggressive breast cancer may result from enhanced inflammatory responses which can augment the carcinogenic pro-inflammatory milieu, and/or from vitamin D deficiency due to high skin pigmentation. Using the pooled resources from four of the largest studies of breast cancer in AA women, we will address these aims by first measuring serum levels of vitamin D (25OH-D) and a panel of 30 immune/inflammatory markers among 800 AA and 800 EA controls, comparing by ancestry, using ancestry Informative markers. Relationships between serum markers and SNPs, as well as epidemiologic factors will be evaluated. We will build a predictive model for vitamin D and use those scores to evaluate relationships with breast cancer subgroups in case-control comparisons. Finally, we will evaluate SNPs in the same panel of immune inflammatory markers and vitamin D metabolism and signaling pathways in relation to breast cancer subgroups in our pooled data of 5,534 AA cases and 5,534 controls. Using our results, we will conduct cross-Project aims to examine associations between breast cancer subgroups and interactions between inflammatory pathways, parity and breastfeeding (Project 2);body size and vitamin D pathways (Project 3);and genetic susceptibility alleles In relevant pathways and inflammatory and vitamin D pathway susceptibility markers. We believe that our novel, but biologically sound hypotheses may reveal risk factors for early, aggressive cancer that can be acted upon for prevention.